The present invention provides an alternative process and intermediates for the synthesis of 6-alpha-and 6-beta-(aminomethyl)penicillanic acid 1,1-dioxide esters which are hydrolyzable under physiological conditions. This process is of particular value in the synthesis of those hydrolyzable esters, such as the (5-methyl-1,3-dioxol-2-on-4-yl)methyl, ##STR1## and the 1H-isobenzofuran-3-on-1-yl, ##STR2## esters, which tend to be lost in alternative processes which employ a hydrogenolysis step.
My co-pending U.S. patent application Ser. No. 434,371, filed Oct. 21, 1982 discloses compounds of the formulae ##STR3## wherein R.sup.1 is hydrogen or a conventional ester forming radical which is hydrolyzable under physiological conditions. That application also discloses the utility of these compounds, particularly as beta-lactamase inhibitors used in therapy in combination with beta-lactam antibiotics. That earlier application also describes a process and intermediates for the ester compounds (I) and (II) which (like the present process) employs the acid compounds (I) and (II) [R.sup.1 =H] as starting material, but (unlike the present process) includes a hydrogenolysis step.
My co-pending application, Ser. No. 501,476, filed June 6, 1983 describes an alternative process for the above 6-alpha-(aminomethyl)penicillanic acid 1,1-dioxide esters; and the co-pending application of Pirie et al., Ser. No. 501,475, also filed June 6, 1983 describes yet another process for both of the above 6-alpha- and 6-beta-(aminomethyl)penicillanic acid 1,1-dioxide esters.
In all of the above cited processes, those in vivo hydrolyzable groups which do not tend to be removed under the hydrogenolysis conditions used in their preparation are preferred. Thus the present process is particularly advantageous in now allowing the efficient synthesis of in vivo hydrolyzable esters which are susceptible to such hydrogenolysis, in particular the efficient synthesis of 1H-isobenzofuran-3-on-1-yl and (5-methyl-1,3-dioxol-2-on-4-yl)methyl 6-(aminomethyl)penicillanate 1,1-dioxides.
Other compounds previously reported as beta-lactamase inhibitors useful in combination with beta-lactam antibiotics for the treatment of bacterial infections include penicillanic acid 1,1-dioxide and esters thereof readily hydrolyzable in vivo (Barth, U.S. Pat. No. 4,234,579); the bis-methanediol ester of sulbactam (Bigham, U.S. Pat. No. 4,309,347); various 6-beta-(hydroxymethyl)penicillanic acid 1,1-dioxides and esters thereof (Kellogg, U.S. Pat. No. 4,287,181); and 6-beta-(aminomethyl)penicillanic acid (McCombie, U.S. Pat. No. 4,237,051). Talampicillin (USAN generic name), the 1H-isobenzofuran-3-on-1-yl ester of ampicillin (Clayton et al., J. Med. Chem., 19, pp. 1385-1390, 1976), and (5-methyl-1,3-dioxiol-3-on-4-yl)methyl ester of ampicillin (Sakamoto et al., U.S. Pat. No. 4,342,693) exemplify those in vivo hydrolyzable ester radicals of particular interest in the present case. Above cited Clayton et al. also illustrates various crotonolactonyl and butyrolactonyl esters of ampicillin as in vivo hydrolyzable esters.
U.K. Pat. No. 2,053,220, published Feb. 4, 1981, broadly discloses beta-lactamase inhibiting compounds of the formula ##STR4## The definitions of R.sub.a, R.sub.b and R.sub.c define literally an infinite number of compounds. These definitions, by appropriate selection of R.sub.a, R.sub.b and R.sub.c, may possibly define the 6-alpha-(aminomethyl)penicillanic acid 1,1-dioxides of present interest. No specific method for preparation of these compounds is present in the disclosure of this U.K. application, and there is no hint or suggestion that from among the infinity of compounds proposed, the present aminomethyl compounds are preferred compounds, possessing the particularly highly potent beta-lactamase inhibitory activity which we have determined for them.